Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Neuroscience. 2018 Sep 15;388:448-459. doi: 10.1016/j.neuroscience.2018.08.004. Epub 2018 Aug 16.
Anxiety disorder is a major psychiatric disorder characterized by fear, worry, and excessive rumination. However, the molecular mechanisms underlying neural plasticity and anxiety remain unclear. Here, we utilized a mouse model of anxiety-like behaviors induced by the chronic administration of corticosterone (CORT) to determine the exact mechanism of each region of the fear circuits in the anxiety disorders. Chronic CORT-treated mice showed a significant increase in anxiety-related behaviors as assessed by the elevated plus maze, light-dark, open-field, and marble-burying tasks. In addition, chronic CORT-treated mice exhibited abnormal amygdala-dependent tone-induced fear memory but normal hippocampus-dependent contextual memory. Consistent with amygdala hyperactivation, chronic CORT-treated mice showed significantly increased numbers of c-Fos-positive cells in the basolateral amygdala (BLA) after tone stimulation. Long-term potentiation (LTP) was markedly enhanced in the BLA of chronic CORT-treated mice compared to that of vehicle-treated mice. Immunoblot analyses revealed that autophosphorylation of Ca/calmodulin-dependent protein kinase (CaMK) IIα at threonine 286 and phosphorylation of cyclic-adenosine-monophosphate response-element-binding protein (CREB) at serine 133 were markedly increased in the BLA of chronic CORT-treated mice after tone stimulation. The protein and mRNA levels of brain-derived neurotrophic factor (BDNF) also significantly increased. Our findings suggest that increased CaMKII activity and synaptic plasticity in the BLA likely account for the aberrant amygdala-dependent fear memory in chronic CORT-treated mice.
焦虑障碍是一种主要的精神障碍，其特征是恐惧、担忧和过度沉思。然而，神经可塑性和焦虑的分子机制尚不清楚。在这里，我们利用皮质酮（CORT）慢性给药诱导的焦虑样行为小鼠模型，确定了恐惧回路各个区域在焦虑障碍中的确切机制。慢性 CORT 处理的小鼠在高架十字迷宫、明暗箱、旷场和埋珠任务中表现出明显增加的焦虑相关行为。此外，慢性 CORT 处理的小鼠表现出杏仁核依赖性音调诱导的恐惧记忆异常，但海马依赖性情境记忆正常。与杏仁核过度激活一致，慢性 CORT 处理的小鼠在音调刺激后显示出基底外侧杏仁核（BLA）中 c-Fos 阳性细胞数量显著增加。与对照组相比，慢性 CORT 处理的小鼠的 BLA 中长时程增强（LTP）明显增强。免疫印迹分析显示，在音调刺激后，慢性 CORT 处理的小鼠的 BLA 中 Ca/calmodulin 依赖性蛋白激酶（CaMK）IIα 的苏氨酸 286 位自动磷酸化和环腺苷酸反应元件结合蛋白（CREB）的丝氨酸 133 位磷酸化显著增加。脑源性神经营养因子（BDNF）的蛋白和 mRNA 水平也显著增加。我们的研究结果表明，BLA 中 CaMKII 活性和突触可塑性的增加可能是慢性 CORT 处理的小鼠出现异常杏仁核依赖性恐惧记忆的原因。
